We used laser capture microdissection to obtain enriched populations of tumor epithelial cells and adjacent stromal cells from 15 patients with IBC and 35 patients with invasive breast cancer (non-IBC) and determined the mRNA expression profile. Previously established classifiers for IBC and poor breast cancer survival were evaluated in our data set. We found that the gene expression profile of the tumor stroma distinguishes between IBC and non-IBC. Furthermore, a previously published IBC prediction signature performed better in classifying IBC using the gene expression profile of the tumor stroma than the profile of the tumor epithelium. A validated survival gene signature derived from a human fibroblast serum response classified poor versus good survival with high accuracy using the expression profile of the tumor stroma. Additional pathway analysis showed that the expression differences in the IBC versus non-IBC contrast cluster in distinct pathways. We identified genes and pathways that could be functionally significant in stromal cells of IBC. In summary, genes in the tumor-adjacent stroma may have a key role in determining breast cancer phenotypes and disease aggressiveness. Interindividual differences in host genetics may exist that alter the transcriptome of stromal cells and predispose individuals to a metastatic disease.